In these studies we have explored the response of smooth muscle cells isolated from the aortas of rats and grown in culture to various receptor agonists. Beta-agonists strongly stimulate the accumulation of cAMP but have little effect on intracellular free calcium. In contrast, angiotensin II and arginine vasopressin cause rapid and marked increases in intracellular free calcium but have little effect on the accumulation of cAMP. In the case of arginine vasopressin, the enhancement of intracellular calcium was dependent entirely upon extracellular calcium. In contrast, angiotensin II apeared to stimulate both uptake of extracellular calcium and release of intracellular calcium. An examination of phosphotidylinositol turnover revealed that this biochemical event was closely correlated with the accumulation of intracellular calcium, both events were blocked by the appropriate antagonist. Additional studies have now shown that angiotensin II, which has little effect on the accumulation of cAMP, strongly potentiates the weak accumulation of cAMP in response to vasoactive intestinal polypeptide. Such a powerful synergism appears to offer an opportunity for further understanding of how neuropeptides interact at their cellular receptor sites.